Although recent years have seen tremendous strides in the understanding of iron metabolism, which remains to be uncovered about the regulation of iron transport and homeostasis in mammalian cells. The present study focuses on the roles of transferrin and the transferrin receptor in managing the delivery of iron to iron-dependent cells. Two collaborative efforts, and one that is largely self-contained, are presented. In the first of these, a largely collaborative study with Project 2 of the Program, the emphasis is on the transferrin-recognition site of the transferrin receptor. The transferrin receptor of iron-requiring cells functions not only to bind and internalize transferrin, but also to modulate iron release from transferrin. Our goal is to determine how the receptor recognizes and binds transferrin, how the receptor-transferrin complex resists disruption within the acidified endosome to which it is internalized, and how the receptor regulates iron release from transferrin in a pH-dependent fashion. Next, in our major undertaking, we seek to understand the molecular events in the receptor-independent pathway exhibited by hepatic cells by securing transferring transferrin- borne iron. This pathways may secure more iron for hepatocytes than the much better understood, and more often studied, receptor-mediated route. In our third undertaking, a joint effort with Project 5 of the Program, we will explore the conformational changes accompanying the binding and release of iron by transferrin. Here, our aim is to unravel the sequences and mechanisms of conformational changes in transferrin. Here, our aim is to unravel the sequences and mechanisms of conformational changes in transferrin Our approach is problem-oriented and multi- disciplinary combining methods of cell biology, molecular biology (mutagenesis), and physical biochemistry to gain information into the fundamental biological processes of iron metabolism.